Trial record 1 of 8 for:    "Methylmalonic acidemia"
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Long-term Outcome of N-Carbamylglutamate Treatment in Propionic Acidemia and Methylmalonic Acidemia

This study is currently recruiting participants.
Verified July 2013 by Children's Research Institute
Sponsor:
Collaborators:
Children's Hospital Boston
University Hospitals of Cleveland
Children's Hospital of Colorado
University of California, Los Angeles
Children's Hospital of Philadelphia
Seattle Children's Hospital
Information provided by (Responsible Party):
Children's Research Institute
ClinicalTrials.gov Identifier:
NCT01597440
First received: May 10, 2012
Last updated: September 3, 2013
Last verified: July 2013
  Purpose

Background: Very few drugs exist that treat hyperammonemia, specifically PA and MMA. Diet restrictions and alternate pathway agents are the current primary treatments, but they frequently fail to prohibit brain damage.

Orthotopic liver transplantation cures the hyperammonemia of urea cycle disorders, but organ availability is limited and the procedure is highly invasive and requires life-long immunosuppression.

A drug that could repair or stimulate a dysfunctional urea cycle such as this would have several advantages over current therapy. A drug called N-carbamyl-L-glutamate, Carglumic acid (NCG or Carbaglu)has recently been found to be virtually curative of another urea cycle defect called NAGS deficiency. In this disorder, treatment with NCG alone normalizes ureagenesis, blood ammonia and glutamine levels, allows normal protein tolerance and restores health. Knowledge from this study is being applied to acquired hyperammonemia, specifically in patients with propionic PA and MMA, to try and improve neurodevelopmental outcomes by improving the hyperammonemia.

Aims: The overall objective of this project is to determine whether treatment of acute hyperammonemia with Carglumic acid in propionic acidemia (PA), methylmalonic acidemia (MMA) changes the long-term outcome of disease and to determine if it is effective in restoring urine ammonia levels to normal levels.


Condition Intervention Phase
Propionic Acidemia (PA)
Methylmalonic Acidemia (MMA)
Drug: N-carbamylglutamate
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Long-term Outcome of N-Carbamylglutamate Treatment in Propionic Acidemia and Methylmalonic Acidemia

Resource links provided by NLM:


Further study details as provided by Children's Research Institute:

Primary Outcome Measures:
  • Neurodevelopment [ Time Frame: Intake through 7 days or discharge ] [ Designated as safety issue: No ]
    Neurodevelopmental outcome as measured by Cognitive Composite (Bayley III), Motor Composite (Bayley III) and Functional Status Scale and safety of NCG treatment as measured by adverse events and laboratory blood tests


Secondary Outcome Measures:
  • Safety and Efficacy [ Time Frame: Intake through 7 days or discharge ] [ Designated as safety issue: Yes ]
    Safety as measured by adverse events. Efficacy as measured by resolution of hypoammonemia.


Estimated Enrollment: 34
Study Start Date: September 2012
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Carbaglu
Active NCG & Standard of Care
Drug: N-carbamylglutamate

Chemical Composition: N-carbamyl-L-glutamic acid (NCG) The daily dose will be 100 mg/kg/ day. The doses are to be divided into 2 equal doses and administered orally or enterally by nasogastric or gastrostomy tube (standard of care will prevail when choosing the mode of drug administration).

The tablets must be dispersed in a minimum of 2.5-10 ml of water and ingested immediately or administered by fast push through a syringe via a nasogastric or gastrostomy tube. The suspension has a slightly acidic taste.

This drug will be administered for 7 days after admission or until discharge (whichever is sooner).

Other Names:
  • Carbaglu
  • NCG
Placebo Comparator: Placebo
Standard of Care therapy

Detailed Description:

Methods/Design This 5-year, Phase II, double-blind study aims to recruit and enroll 34 PA and MMA patients during acute episodes of hyperammonemia.

The primary aim is to circumvent the long-term neurodevelopmental decline due to having a prolonged levels of ammonia during crisis in the blood and urine. After treatment and crisis resolution with Carbaglu or placebo and standard of care therapy, measures of neurodevelopmental outcomes (Bayley II and Functional Status Scale) are being measured at 9, 15,21 and 30 months post-discharge from the hospital. Safety of NCG treatment will also be monitored as measured by close examination of adverse events and laboratory blood tests. To test for the effectiveness of NCG, longitudinal models to evaluate the groupwise difference (NCG vs. Placebo) in the trajectory of change in neurodevelopmental outcomes and safety analyses between drug and placebo patients.

Subsequent Episodes At any time after the initial episode, participants may present to the hospital with PA- or MMA-associated symptoms. If the plasma ammonia level verified as a bonafide episode of HA (plasma ammonia is ≥ 100 µmol/l), that participant will receive the same study medication that they received during their initial episode in a double-blinded fashion, (i.e. If the participant received NCG at the time of initial randomization, he/she will continue to receive NCG at each subsequent HA episode. If the participant received PLBO at the time of initial randomization, he/she will continue to receive PLBO at each subsequent HA episode). Only the pharmacist will know if the participant receives NCG or PLBO. The same study assessments (previously stated) will be conducted at each qualifying HSA episode.

  Eligibility

Ages Eligible for Study:   up to 4 Weeks
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Aged 4 weeks or younger
  • > 36 weeks gestational age at birth
  • Birth weight ≥ 2500 g
  • First clinical presentation plasma ammonia level at presentation >150 µmol/l; subsequent episode eligibility at ammonia >=100
  • PA or MMA presumed or established diagnosis as follows (one of the following):

    1. Acidosis at presentation, pH < 7.3 OR
    2. Plasma acylcarnitine analysis either alone or as part of newborn screening, demonstrating C3 > 4 µmol /liter OR
    3. Diagnosed with PA by quantitative urine organic acid analysis, defined as presence of elevated methylcitric acid and normal methylmalonic acid levels and no evidence of biotin related disorders in the organic acid analysis OR
    4. Diagnosed with MMA by quantitative urine organic acid analysis, defined as elevation of methylmalonic acid and no evidence of vitamin B12 dependent disorder on plasma amino acid analysis
  • Able to receive medications orally, by nasogastric (NG) tube or by Gastric (G)-tube
  • No concomitant illness which would preclude safe participation as judged by the investigator
  • Signed informed consent by the subject's legally acceptable representative
  • After initial enrollment, criteria 3 or 4 (definitive diagnosis) must be fulfilled prior to discharge from initial admission in order to remain in the study.

Exclusion criteria

  • Administration of NCG within 7 days of enrollment into the study
  • Use of any other investigational drug, biologic, or therapy, with the exception of sodium benzoate or sodium phenylacetate administered prior to diagnosis by acyl carnitine analysis (diagnostic inclusion criterion 2), or organic acid analysis (diagnostic inclusion criteria 3

    • 4)
  • Diagnosis of any medical condition causing hyperammonemia which is not PA or MMA.
  • Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may put the subject at an additional risk by participating in this study
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01597440

Locations
United States, California
University of California Los Angeles Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Naghmeh Dorrani, MS, CGC    310-825-8084    Ndorrani@mednet.ucla.edu   
Principal Investigator: Derek Wong, MD         
Lucile Packard Children's Hospital at Stanford Not yet recruiting
Palo Alto, California, United States, 94304
Principal Investigator: Gregory M Enns, MD         
United States, Colorado
The Children's Hospital of Colorado Not yet recruiting
Aurora, Colorado, United States, 80045
Contact: Curtis R Coughlin, MS, CGC    303-724-2310    Coughlin.Curtis@tchden.org   
Principal Investigator: Renata C Gallagher, MD, PhD         
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Sandra Yang, MS, CGC    202-476-5566    syang@childrensmational.org   
Principal Investigator: Nicholas Ah Mew, MD         
United States, Massachusetts
Children's Hospital Boston Not yet recruiting
Boston, Massachusetts, United States, 02115
Contact: Stephanie Newton, MS, CGC    617-919-4790    Stephanie.Newton@childrens.harvard.edu   
Principal Investigator: Gerard T Berry, MD         
United States, Ohio
University Hospitals of Cleveland/Rainbow Babies and Children's Hospital Not yet recruiting
Cleveland, Ohio, United States, 44106
Contact: Christine W Heggie, RN, ND    216-844-7124    christine.heggie@uhhospitals.org   
Principal Investigator: Shawn McCandless, MD         
United States, Pennsylvania
The Children's Hospital of Philadelphia Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Irma Payan, RN, PNP    215-590-6236    Payan@email.CHOP.edu   
Principal Investigator: Marc Yudkoff, MD         
Sponsors and Collaborators
Children's Research Institute
Children's Hospital Boston
University Hospitals of Cleveland
Children's Hospital of Colorado
University of California, Los Angeles
Children's Hospital of Philadelphia
Seattle Children's Hospital
Investigators
Principal Investigator: Mendel Tuchman, MD Children's Research Institute
  More Information

No publications provided

Responsible Party: Children's Research Institute
ClinicalTrials.gov Identifier: NCT01597440     History of Changes
Other Study ID Numbers: NCGC 0007
Study First Received: May 10, 2012
Last Updated: September 3, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Children's Research Institute:
Propionic acidemia (PA)
Methylmalonic acidemia (MMA)
Carbaglu NCG
Hyperammonia

Additional relevant MeSH terms:
Acidosis
Propionic Acidemia
Amino Acid Metabolism, Inborn Errors
Acid-Base Imbalance
Metabolic Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn

ClinicalTrials.gov processed this record on April 17, 2014